Дисертації з теми "KIT tyrosine kinase"
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Edling, Charlotte. "Receptor tyrosine kinase c-Kit signalling in hematopoietic progenitor cells." Doctoral thesis, Umeå : Umeå University, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-888.
Повний текст джерелаRead, Stuart Hamilton. "Production and function of a soluble c-Kit molecule." Title page, abstract and contents only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phr2845.pdf.
Повний текст джерелаShulman, Johanna. "Biochemical analysis of activating mutations of the kit receptor tyrosine kinase." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0003/MQ40794.pdf.
Повний текст джерелаRosnet, Olivier. "Caractérisation d'un recepteur à tyrosine kinase apparenté à KIT et FMS." Aix-Marseille 2, 1993. http://www.theses.fr/1993AIX22045.
Повний текст джерелаLermet, Anne. "Synthèse d'inhibiteurs de la protéine à activité tyrosine kinase c-kit de type sauvage et muté." Lyon 1, 2006. http://www.theses.fr/2006LYO10026.
Повний текст джерелаCambareri, Antony Charles. "Molecular and cellular studies examining the biological significance of different isoforms of the receptor tyrosine kinase, c-Kit /." Title page, table of contents and abstract only, 2004. http://web4.library.adelaide.edu.au/theses/09PH/09phc174.pdf.
Повний текст джерелаBaker, Clare V. H. "XKrk1, a c-kit-related receptor tyrosine kinase expressed in Xenopus embryos." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338070.
Повний текст джерелаAndré, Catherine. "Les oncogenes c-kit et c-fms : recepteurs a activite tyrosine kinase." Paris 7, 1992. http://www.theses.fr/1992PA077214.
Повний текст джерелаAn, Ningfei, Bo Cen, Houjian Cai, Jin H. Song, Andrew Kraft, and Yubin Kang. "Pim1 kinase regulates c-Kit gene translation." BIOMED CENTRAL LTD, 2016. http://hdl.handle.net/10150/622957.
Повний текст джерелаLarrue, Clément. "Régulation de l'expression protéique des récepteurs à activité tyrosine kinase FLT3 et KIT dans les leucémies aigües myéloïdes." Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30195.
Повний текст джерелаFLT3-ITD and KITD816V mutations are recurrently found in acute myeloid leukemia, where they are associated with a poor prognosis. These two Tyrosine Kinase Receptors (TKR) are involved in leukemogenesis, regulating proliferation, survival and cell differentiation. The aim of this thesis was to study the regulation of FLT3 protein expression in response to proteasome inhibitors, the role of autophagy in KITD816V-driven AML and the impact of 2-deoxy-D-glucose (2-DG) on the intracellular localization of TKRs. Our studies investigated three original ways to target cells bearing FLT3-ITD or oncogenic KIT mutations playing on their degradation, intracellular localization and autophagy
Bachet, Jean-Baptiste. "Récepteurs tyrosine-kinase, voies de signalisation et tumeurs digestives." Versailles-St Quentin en Yvelines, 2013. http://www.theses.fr/2013VERS0019.
Повний текст джерелаReceptor tyrosine kinases (RTKs) are pro-oncogenes involved in the pathogenesis of many gastrointestinal tumors. We conducted several studies of translational and basic research on the RTK KIT and the gastrointestinal stromal tumors (GISTs). GISTs with delWK557-558 and those with a deletion carrying the two tyrosine residues in KIT exon 11 had the same prognosis. Homozygous GISTs appear more often malignant than heterozygous GISTs. We then reported that homozygous GISTs may be secondary to loss of heterozygosity without loss of genetic material. From cell lines, we demonstrated that the biology of KIT in heterozygous cells was closer to that hemizygous unmutated KIT cells that hemizygous mutated KIT. The hemizygous/heterozygous status on the one hand and the loss or non-tyrosine residues of the KIT exon 11 on the other hand were associated with specific expression profiles of mRNA and miRNAs. Finally, we have described three families with a germline mutation in exon 13 of KIT, and we proposed recommendations for their management
Caruana, Georgina. "The transforming potential and functional analysis of the c-Kit receptor tyrosine kinase and its natural occurring isoforms /." Title page, abstract and contents only, 1996. http://web4.library.adelaide.edu.au/theses/09PH/09phc329.pdf.
Повний текст джерелаCopy of author's previously published article inserted into back cover pocket. Includes bibliographical references (leaves 157-214).
Lam, Lily Po Yee. "A transforming mutation induces dimerization and enhances activity of the c-kit soluble tyrosine kinase domain." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq28773.pdf.
Повний текст джерелаCASTERAN, NATHALIE. "Etude fonctionnelle de deux recepteurs hematopoietiques a activite tyrosine kinase de classe iii : kit et flt3." Paris 7, 1997. http://www.theses.fr/1997PA077100.
Повний текст джерелаLe, Gall Marianne. "Etude fonctionnelle des formes oncogéniques de KIT : Nouvelles stratégies d'inactivation de la signalisation oncogénique KIT." Phd thesis, Université Paris Sud - Paris XI, 2014. http://tel.archives-ouvertes.fr/tel-00993493.
Повний текст джерелаMacêdo, Thais Rodrigues. "Comparação da eficácia do mesilato de imatinibe com a vimblastina associada a prednisona no tratamento do mastocitoma canino: estudo clínico, histopatológico, imunohistoquímico e molecular." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/10/10137/tde-05012015-094225/.
Повний текст джерелаThe objective of this study was to evaluate the efficacy of imatinib mesylate, compared with the usual chemotherapy with vinblastine and prednisone in the treatment of canine mast cell tumor and describe the side effects submitted by medications. Well as analyzing the expression of VEGF (vascular endothelial growth factor), the relationship between the expression of c-kit gene by RT-PCR and immunohistochemical staining of KIT with the presence of mutations in the juxtamembrane and the relationship of this mutation with response to therapy. For both 29 animals with cytological diagnosis of mast cell tumor were included, these animals underwent computed tomography to determine the measured skin formations and then divided into 2 groups. Group 1 was treated with the chemotherapeutic protocol vinblastine and prednisone for 12 weeks and the second group with the imatinib mesylate in a dose of 10 mg / kg every 24 hours for 8 weeks. The assessment of response to treatment was performed with periodic measurements of the formations Caliper and a new computed tomography in the end of treatment to measure the largest tumor diameter and volume. A fragment of skin formations was collected before the initiation of treatment for histological grading, determination of mitotic index, KIT and VEGF staining patterns and the proliferation marker Ki67. Part of the collected material was extracted RNA and DNA and subsequent sequencing of 11 exons of the c-kit gene and determination and expression of its ligand by RT-PCR. The medication toxicity was evaluated according to the standards of VCOG 1.1.A response rate of the VP group was 7.7% and 28.6% MI group, although patients treated with imatinib had a higher chance of response therapy, no difference in response between the two groups was observed. The two protocols were well tolerated, patients in the MI group had a smaller number of side effects. The histological grade, mitotic index, staining patterns KIT, beyond the quantification of Ki-67 were homogeneous in both groups and did not influence the response to treatment. Quantification of VEGF was intensely in patients with partial and total remission. It was no relationship between KIT and quantification of the expression of c-kit gene, which was higher in patients who responded to treatment, but its association with response to therapy cant be determined. Exon11 activating mutations in the c-kit gene were not identified. Treatment with imatinib mesylate is well tolerated by the animals, however this was not superior to standard chemotherapy protocol for the treatment of mast cell tumors; this result may have been influenced by the number of animals included in the study. Mutations in other domains of the KIT receptor and action in ITK receptors as PDGF and VEGF may be related to response to this class of drugs in this study, despite the absence of activating mutations in exon 11 of c-kit gene.
Klüppel, Michael. "Analysis of regulatory W mutations and the function of the Kit receptor tyrosine kinase in the intestine." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq35208.pdf.
Повний текст джерелаChaix, Amandine. "Les spécificités de la signalisation oncogénique par rapport à la signalisation physiologique : le modèle de KIT, un récepteur à activité tyrosine kinase." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX22079/document.
Повний текст джерелаThe receptor tyrosine kinase KIT and its ligand, the stem cell factor (SCF), are implicated both in the development and the homeostasis of multiple cell lineages. Dysfunctions in the KIT/SCF pathway are involved in several pathologies affecting these compartments. In particular, gain-of-function mutations that lead to constitutive activation of the receptor KIT are found in human neoplasia.The purpose of this thesis project was to investigate some differences between normal and oncogenic signalling of KIT receptor using mast cells transformed by the KIT-D816 oncogene as a model. This question was analysed at aproximal level on the oncogenic receptor itself and at a more distal level on the STAT signal transduction pathway, which is specifically and constitutively activated by theKIT-D816 mutant.At the proximal level, we show that the juxtamembrane dityrosine motif Y568-Y570 of KIT is the major platform of recruitment of intracellular signalling partnerswith more than 15 interactors found in mast cells. Furthermore, the analysis ofcellular models in both in vitro and in vivo assays related to KIT physiological functions has revealed the negative role of the motif in KIT-D816-mediated cell transformation. At the distal level, we have analysed the mechanisms of phosphorylation ofSTAT1, -3 and -5 proteins and the functional relevance of their activation in KITD816-mediated transformation. We describe the contribution of different kinases inthe phosphorylation of STATs on both serine and tyrosine residues. Our results suggest that only STAT5 is transcriptionaly active whereas STAT1 and STAT3 are not, suggesting a non conventional implication of their activation in celltransformation. Our work contributes to a better understanding of the mechanisms of KITD816-mediated oncogenesis and could be used to improve the rational developmentof new targeted cancer therapies
Lin, Tzu-yin. "The world according to mast cells the role of Kit in normal and neoplastic canine mast cells /." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1189098916.
Повний текст джерелаVoisset, Edwige. "Etude de l'implication des protéines fes et fer dans la signalisation des recepteurs à activité tyrosine kinase kit et FLT3." Aix-Marseille 2, 2008. http://theses.univ-amu.fr.lama.univ-amu.fr/2008AIX22027.pdf.
Повний текст джерелаFraser, Lindsay. "Role of the SCF/KIT signalling pathway in embryonic stem cells." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5564.
Повний текст джерелаSepulveda, Paulo De. "Etude genetique et moleculaire de c-kit, le gene codant pour le recepteur a activite tyrosine kinase du facteur scf." Paris 7, 1996. http://www.theses.fr/1996PA077130.
Повний текст джерелаTonary, Angela Marie. "Expression, regulation, and function of the KIT tyrosine kinase receptor and its ligand, stem cell factor, in human epithelial ovarian cancer." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ58295.pdf.
Повний текст джерелаVINCENT, STEPHANE. "Interaction entre le recepteur a tyrosine kinase kit et son ligand kl au cours de la meiose chez la souris male." Nice, 1999. http://www.theses.fr/1999NICE5360.
Повний текст джерелаSardinha, Ruth Andreia Henriques. "Molecular study of therapeutic targets of tyrosine kinase inhibitors in endometrial stromal tumors: molecular and protein expression of kit, PDGFRA and EGFR." Doctoral thesis, Universidade de Évora, 2014. http://hdl.handle.net/10174/11414.
Повний текст джерелаBernex, Florence. "Etude fonctionnelle de c-kit, le gene codant pour le recepteur a activite tyrosine kinase du facteur scf chez l a souris." Paris 6, 1996. http://www.theses.fr/1996PA066764.
Повний текст джерелаLeiras, Pedro Leonardo dos Santos David Torres. "Clínica e cirurgia de animais de companhia: mastocitoma canino." Master's thesis, Universidade de Évora, 2014. http://hdl.handle.net/10174/13513.
Повний текст джерелаTisserand, Julie. "Mise en évidence d'un rôle suppresseur de tumeur pour la protéine tyrosine-kinase FES dans le mélanome." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM5035.
Повний текст джерелаAmong skin cancers, melanoma is the most aggressive and has the worst prognosis. In the last years, new therapeutic tools have been developed but responses differ between patients and are often transient due to resistance mechanisms. This highlights the need to improve understanding of molecular mechanisms of the disease. During my thesis, I have shown for the first time that FES tyrosine kinase is expressed in normal melanocytes, and that its expression is lost at the protein and RNA levels in most melanoma cell lines. The same result is observed in a panel of 12 patients’ short-term cultures. The lack of expression is due to FES promoter hyper-methylation and can be reverted using a hypomethylating agent. By restoring FES expression in two melanoma cell lines, I observe a decrease of oncogenic properties of the cells. Moreover, the analysis of the TCGA data on melanoma indicate that FES expression is strongly decreased or lost in about 40% of patients, and that this loss of expression is correlated with FES promoter methylation. Importantly, patients with low level of FES mRNA have poor prognosis compared to FES expressing patients. Finally, Fes knock-out mice crossed with an inducible melanoma mouse model indicate that tumors proliferation and size are more important under a Fes KO background.In conclusion, by using melanoma cells in vitro, data from melanoma patients and mouse models, I have demonstrated that FES is expressed in normal melanocytes and clearly plays a tumor suppressor role.in melanoma
Dos, Santos Cédric. "Activation anormale de la tyrosine kinase Lyn et de la voie PI3K/Akt dans les leucémies aiguës myéloïdes (LAM) et ciblage pharmacologique." Toulouse 3, 2008. http://www.theses.fr/2008TOU30220.
Повний текст джерелаAcute Myeloid Leukemia (AML) is a clonal hematopoietic disorder characterized by an accumulation of immature leukemic cells an by a block in differentiation. The molecular basis of AML is thougt to arise at the hematopoietic stem or committed progenitors level by the acquisition of at least two types of crucial cooperating mutations. Class I mutations, affecting receptor tyrosine kinases and key components of signalling pathways, conferring growth and proliferative advantages, are associated with class II mutations affecting transcription factors, leading to impaired normal differentiation program. The signalling pathway mTOR/S6K/4E-BP1, involved in the control of translation, growth and apoptosis, is found constitutively activated in about 70% of primary leukemic samples. The aim of this study was first to characterize the molecular mechanism of this constitutive activation patwhay and second to check tyrosine kinases involvement in AML. Compared to normal hematopoietic progenitors CD34+, we have shown that Src kinases family members (SFKs), especially Lyn, are constitutively overactivated in all primary leukemic samples tested, including the small contingent of CD34+ CD38- CD123+ cells which is thought to be the leukemic stem cell compartment. By using pharmacological and siRNA approaches, we were able to demonstrate that Lyn plays a major role in the AML pathophysiology, at least by regulating the mTOR/S6K/4E-BP1pathway activity. This work establish Lyn kinase as a relevant new therapeutic target in the treatment of AML. Then, we assessed the putative implication of several transduction pathways acting upstream of mTOR in AML, especially the PI3K/Akt patway as it has been largely described in solid tumors. Compared to normal hematopoietic progenitors, the PI3K/Akt pathway is strongly activated in AML as we found a high level of the PI3K products and the phosphorylation status of Akt on both threonine 308 (Thr 308) and serine 473 (Ser 473) residues. .
Tinsley, S. P. "To establish the role of mutations in c-KIT tyrosine kinase in the pathogenesis and therapy of core-binding factor-related acute myeloid leukaemia (AML)." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1433249/.
Повний текст джерелаPaula, Beatriz Quintino Rogado Mendes. "Padrão de expressão do recetor KIT no mastocitoma canino : seleção dos inibidores dos recetores tirosina quinase." Master's thesis, Universidade de Lisboa, Faculdade de Medicina Veterinária, 2018. http://hdl.handle.net/10400.5/16667.
Повний текст джерелаOs mastocitomas representam cerca de 11 a 27% de todas as neoplasias cutâneas malignas do cão. Devido à sua prevalência e comportamento biológico variável, ao custo da terapêutica e ao potencial stress emocional para os tutores, é importante realizar um prognóstico preciso dos mastocitomas cutâneos e selecionar corretamente a abordagem terapêutica mais apropriada. Vários fatores clínicos podem influenciar o curso da doença, no entanto, o fator de prognóstico mais importante é a gradação histológica. As mutações no c-kit e as alterações da expressão do KIT são conhecidas como indicadores de prognóstico negativo em mastocitomas cutâneos caninos. Além disso, animais portadores de mastocitomas com mutações no c-kit ou padrões de expressão anormais do KIT são potenciais candidatos à terapêutica alvo com inibidores dos recetores tirosina quinase (IRTQ). O principal objetivo deste estudo foi selecionar o melhor IRTQ para cada caso, com base no padrão de expressão do KIT. Um objetivo adicional foi a identificação e avaliação de fatores influenciadores de prognóstico, através de associações estatísticas e da análise de sobrevivência. Os 42 casos de animais com mastocitomas investigados foram, inicialmente, distribuídos por sexo, idade, raça, localização, tipo de lesão e grau histológico do tumor e, ainda, padrão de expressão do KIT. A idade do animal mostrou associação significativa com o grau histológico (p=0,0495) e a localização tumoral com o padrão de expressão do KIT (p=0,0271). Além disso, o risco de desenvolvimento de tumores com padrões do KIT atípicos foi superior nos animais com idades superiores a 8 anos, lesões múltiplas e tumores de alto grau histológico. Como bons indicadores influenciadores de prognóstico identificaram-se a idade no momento do diagnóstico (p=0,01) e o grau histológico do tumor (p=0,002). O risco de morte, relacionada com o mastocitoma, foi superior nos animais com tumores com padrões do KIT atípicos. As variáveis que apresentaram impacto significativo no tempo de sobrevivência foram a idade, o grau histológico, o tratamento quimioterápico e o tratamento com IRTQ. Foram, ainda, obtidos melhores resultados nas fêmeas e nos mastocitomas com padrão de expressão 1. Apesar das limitações do estudo, os resultados obtidos podem contribuir para o estabelecimento de um prognóstico e para a escolha da terapêutica a implementar em casos de mastocitoma cutâneo canino.
ABSTRACT - KIT expression in canine mast cell tumour: tyrosine kinase inhibitors selection - Mast cell tumours (MCT) are the most frequently diagnosed malignant skin neoplasm in dogs, representing up to 27% of all canine cutaneous neoplasms. Due to their prevalence and variable biologic behavior, the cost of therapeutics, and the potential emotional stress to owners, it is important to accurately prognosticate cutaneous mast cell tumours and to correctly select the most appropriate therapeutic approach. There are varied clinical factors that may influence the outcome; however, accurate histologic grading remains a cornerstone of MCT prognostication. Mutations in c-kit and altered expression of KIT have been shown to be negative prognostic indicators for canine cutaneous mast cell tumours. Furthermore, those mast cell tumours that have c-kit mutations or abnormal KIT expression are potential candidates for targeted therapy with tyrosine kinase inhibitors. The main goal of this study was to select the best tyrosine kinase inhibitor for each KIT expression pattern. An additional goal was the identification and evaluation of prognosis influencing factors, through statistical associations and survival analysis. The 42 mastocytomas investigated were initially distributed by sex, age, race, location, type of lesion, histological grade and KIT expression. The animal age showed a significant association with the histological grade (p = 0.0495) and the tumor location with the KIT expression (p = 0.0271). In addition, the risk of developing tumors with atypical KIT patterns was higher in animals aged over 8 years, with multiple lesions and tumors of high histological grade. The age at diagnosis (p = 0.01) and the histological grade of the tumor (p = 0.002) showed to be good prognostic indicators. The risk of death related to the mast cell tumour was higher in animals with tumors with atypical KIT patterns. The variables that had a significant impact on survival time were age, histological grade, chemotherapeutic treatment and treatment with tyrosine kinase inhibitors. Better results were also obtained in females and mast cells tumours with expression pattern 1. Lastly, despite the limitations of the study, the results obtained may be useful in establishing a prognosis and in the therapeutic choice in cases of canine cutaneous mast cell tumour.
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Yang, Ying. "Identification et caractérisation fonctionnelle des mutations du gène C-KIT dans des pathologies mastocytaires humaines et canines." Aix-Marseille 2, 2009. http://www.theses.fr/2009AIX20670.
Повний текст джерелаHuman mastocytosis and canine mast cell tumors (MCT) are heterogeneous mast cell diseases and associated with c-kit gain-of-function mutations. In two prospective studies of clinical and genotypic feature of adult and pediatric mastocytosis, we have observed that kit extracellular domain mutations (ECD) and phosphotransferase domain mutations (PTD) are specifically linked with pediatric and adult mastocytosis respectively. Then, analysis of biologic effects of kit mutations revealed at a cellular and a molecular level different functional consequences mediated by ECD mutations versus PTD mutations. Finally, in a kit genotyping study of canine MCT, we delineated the status of kit gain-of-function mutations and elucidated its causative role in this disease. In conclusion, our findings gained insight into pathogenesis of mast cell pathologies and could help to develop new therapeutic strategies
Lennartsson, Johan. "Stem Cell Factor Induced Signal Transduction." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5291-4/.
Повний текст джерелаBibi, Siham. "Nouvelles approches thérapeutiques au cours des mastocytoses systémiques avancées KIT D816V+ résistantes aux inhibiteurs de tyrosine kinases." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS551.
Повний текст джерелаSystemic mastocytosis (SM) is a heterogeneous group of rare diseases characterized by abnormal accumulation of malignant mast cells (MCs) in the bone marrow (BM) and other extra-cutaneous organs. The majority of SM patients have an activating mutation in the KIT gene, usually the D816V point mutation, which is found in more than 90% of all patients. This mutation induces constitutive activation of the KIT receptor by triggering a cascade of signaling pathways, including the PI3K/AKT and the JAK/STAT5 pathways, resulting in the inhibition of apoptosis and increased survival and proliferation of malignant mast cells. However, the efficacy of the tyrosine kinase inhibitors (TKIs) on this mutation is limited due to resistance and/or toxicity associated with a lack of specificity. It is therefore critical to find new therapeutic approaches to overcome this resistance to TKIs, particularly for advanced KIT D816V+ SM. In the present thesis, we have used an approach consisting in targeting molecules activated downstream of KIT D816V, such as AKT and STAT5, using pharmacological inhibitors in combination. This allowed us to identify a synergistic combination of an AKT inhibitor (GSK690693) and an inhibitor of STAT5 (BP-1-102). These compounds are able to inhibit proliferation of KIT D816V+ cells, alone or in combination, but at very high concentrations, unfortunately not useful therapeutically. Nevertheless, these initial results have validated STAT5 and AKT as potential targets for the treatment of advanced SM. The second approach used was to target directly the KIT D816V receptor by pharmacological inhibitors. After a large screening, we identified three compounds - BLU2317, BLU2718 and DCC-2618 - which selectively inhibit the phosphorylation of KIT D816V. These compounds inhibit the proliferation of ROSAKIT D816V and HMC-1.2 cells, and induce apoptosis of these cells in a dose-dependent manner. Although the effects of these three compounds are similar, the DCC-2618 compound acts at lower concentrations relative to BLU2317 and BLU2718 compounds. In order to assess the in vivo efficacy of DCC-2618, we first established a new model of SM based on intravenous injection of cells expressing Gaussia luciferase (Gluc), ROSAKIT D816V-Gluc cells, in NSG mice. The presence of the secreted Gluc in ROSAKIT D816V-Gluc cells facilitates the detection of engraftment and allows precise monitoring of disease progression. This model reproduced within four weeks, in all grafted mice, an advanced SM similar to the one found in humans, with neoplastic MCs infiltration in BM, blood, spleen and liver, while the terminal deterioration of the clinical condition of the mice was observed after 12 weeks. Thus, this new in vivo model allows modulating the aggressiveness of the disease by varying the number of injected cells. It provides sufficient time to explore the kinetics of disease progression and especially to conduct preclinical pharmacological studies. We then evaluated the effect of DCC-2618 compound in vivo on this model. Surprisingly, DCC-2618 was not able to inhibit disease progression in treated mice, although it reached high concentrations in the BM and the plasma of treated mice. Nevertheless, we showed that the compound was able to inhibit the phosphorylation of the KIT receptor in cells derived from the BM of treated mice. In addition, contrasting to the effects observed in vitro, DCC-2618 induced an over-expression of phospho-ERK1/2 in the malignant cells of transplanted mice. This suggests that ERK1/2 may play a critical role in the resistance to DCC-2618, and possibly to other TKIs, independently of the KIT receptor. ERK1/2 could thus be a new interesting therapeutic target in the treatment of advanced SM resistant to TKIs
Fjällskog, Marie-Louise. "Current Medical Treatment of Endocrine Pancreatic Tumors and Future Aspects." Doctoral thesis, Uppsala University, Department of Medical Sciences, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2709.
Повний текст джерелаWe treated 16 patients with somatostatin analogs combined with α-interferon and achieved a biochemical and/or radiological response in 56% (median duration 22 months). We consider this treatment a good alternative for patients who fail during chemotherapy or who do not want to/cannot receive cytotoxic drugs.
Thirty-six patients with neuroendocrine tumors were treated with cisplatin combined with etoposide. Of 14 patients with evaluable EPTs, 50% responded radiologically and/or biochemically (median duration 9 months). We consider this treatment useful as first-line medical treatment in aggressive EPTs or in patients failing prior chemotherapy.
Twenty-eight tumor tissues from EPTs were examined with immunohistochemistry regarding expression of somatostatin receptors (ssts) 1 to 5 on tumor cells and in intratumoral vessels. We found that sst2 and sst4 were highly expressed on tumor cells and in vessels. However, sst3 and sst5 were lacking in half of the tumor tissues and in most of the vessels. Because of the variability in sst expression, we recommend analysis of each individual’s receptor expression before starting treatment.
Endocrine pancreatic tumors (EPTs) are rare with an incidence of 4 per million inhabitants. In the majority of cases they grow slowly, but there are exceptions with very rapidly progressing malignant carcinomas. First-line medical treatment is streptozotocin combined with 5-fluorouracil.
We examined 38 tumor samples regarding expression of tyrosine kinase receptors platelet-derived growth factor receptors (PDGFRs), c-kit and epidermal growth factor receptor (EGFR). We found that the receptors were expressed in more than half of the tumor tissues. Further studies will reveal if tyrosin kinase antagonists can be part of the future treatment arsenal.
Barete, Stéphane. "Implications des tyrosine kinases dans la physiopathologie et la thérapeutique des mastocytoses." Paris 7, 2012. http://www.theses.fr/2012PA077058.
Повний текст джерелаMastocytosis is a heterogeneous disorder characterized by an accumulation of proliferative mast cells with activation in various tissues. Derived from progenitors, mast cells express the membrane KIT receptor encoded by KIT proto-oncogene, which is involved in cellular differentiation and activation. KIT activating mutations, mainly in exon 17 (816 codon position), have been involved in mastocytosis, However, mutation after KIT sequencing analysis is lacking for some affected adults (5% to 30%) and children (14%) (wild type: WT). So, one can speculate that others tyrosine kinases might be involved in pathophysiology of WT mastocytosis. Targeted therapy is an option for indolent systemic mastocytosis (ISM) when symptomatic care is inefficient, to block KIT WT signal transduction and/or proliferation as observed with imatinib. In this work, we have described mast cells precursors and mutations' frequencies among patients cohorts. In another work about WT patients, we have searched in inflltrated tissues (skin and bone marrow) to identify a specific kinase profile comparing to mutated patients. In this transcriptomic study, focused on kinome, our results showed up-regulation of four kinases TK (JAK3, LYN, TEK, IGF1R) in KIT 816 skin. We have then observed in two studies in ISM, a similar efficacy of masitinib, a new tyrosine kinase inhibitor, which might block LYN kinase, independently of KIT mutational status. If these TK might open therapeutic targets for mutated patients, WT mastocytosis pathophysiology remains to be investigated with others research tools
Tabone, Eglinger Séverine. "Étude du proto-oncogène kit dans les tumeurs stromales gastro-intestinales : du patient au modèle cellulaire." Lyon 1, 2008. http://www.theses.fr/2008LYO10039.
Повний текст джерелаCrépin, Ronan. "Génération d'anticorps thérapeutiques par phage display dirigés contre le récepteur de la transferrine et le récepteur Kit." Paris 11, 2010. http://www.theses.fr/2010PA11T081.
Повний текст джерелаSantos, Leticia Rielo de Moura [UNIFESP]. "Expressão imuno-histoquímica da proteína C-kit no Retinoblastoma." Universidade Federal de São Paulo (UNIFESP), 2009. http://repositorio.unifesp.br/handle/11600/9626.
Повний текст джерелаObjetivos: C-kit é uma proteína tirosina–quinase transmembrana que possui importante papel na tumorogênese. Com o desenvolvimento de um novo composto, o mesilato de imatinibe, que inibe especificamente os receptores tirosina quinases, o C-kit passou a ser um importante alvo terapêutico. Nosso objetivo é estudar as características histopatológicas do retinoblastoma, a expressão imuno-histoquímica do C-kit neste tumor e correlacionar esta expressão com os principais fatores prognósticos do retinoblastoma. Material e Métodos: Oitenta e quatro blocos de parafina foram selecionados do arquivo do laboratório de patologia ocular Henry C. Witelson, Montreal, Canada. A imunohistoquímica do C-kit foi realizada de modo automatizado e os resultados foram correlacionados com a idade dos pacientes por ocasião do diagnóstico, grau de diferenciação tumoral e presença ou não de invasão de coróide e nervo óptico. O valor de p menor que 0.05 foi considerado estatisticamente significante. Resultados: A expressão imuno-histoquímica do C-Kit foi observada em 33/63 (52.38%) dos espécimes analisados. Apenas 2 dos 13 (15.4%) tumores que não apresentaram invasão de nervo óptico ou coróide foram positivos para C-kit. Por outro lado, a expressão do C-kit foi observada em 31 (62%) dos 50 tumores que apresentaram algum tipo de invasão seja para coróide ou nervo óptico , 26 dos 44 espécimes com envolvimento de coróide (59.9%), e 20 dos 29 com invasão de nervo óptico (68.96%). Quatorze dos 25 espécimes (56%) moderadamente ou bem diferenciados e 19 dos 38 (50%) pouco diferenciados apresentaram positividade para o C-kit. Dos 41 espécimes provenientes de pacientes com idade superior a 1 ano, e dos 14 (42.80%) com idade até 1 ano a expressão do C-kit foi observada em 21 (51,21%) e 6 (42.80%) espécimes respectivamente. Conclusões: Mais da metade dos retinoblastomas estudados expressaram o C-kit . A expressão do C-kit apresenta correlação estatisticamente significante com a a invasão de nervo óptico.
Purpose: C-kit is a transmembrane tyrosine kinase protein thought to play an important role in tumorigenesis. With the development of the compound Imatinib Mesylate which specifically inhibits tyrosine kinase receptors, C-kit has emerged as a potential therapeutic target. This study aims to determine the immunoexpression of C-kit in retinoblastoma and correlate this expression with histopathological prognostic features. Methods: Eighty-four paraffin-embedded enucleation globes of retinoblastoma were collected from the archives of the Henry C. Witelson Ocular Pathology Registry. C-kit immunostaining was used according to the protocol provided by Ventana Medical System Inc., Arizona. Immunoreactivity was correlated with the presence or absence of invasion into the choroid and optic nerve and the degree of tumour defferentiation. Odds ratios were calculated to quantify differences in C-kit expression between tumours with different patterns of invasion. Results: C-kit expression was identified in 33/63 specimens analysed (53.8%).Two of 13 tumours without choroidal or optic nerve invasio (15.4%) were positive for C-kit. C-kit expression was seen in 31 of the 50 tumours with extraretinal invasion (62%, p<0.01), 26 of 44 specimens with choroidal involvement (59.9%, p<0.02), and 20 of the 29 with optic nerve involvement (68.96%, p<0.02). Fourteen of 25 moderate or well-diferentiated specimens (56%) and 19 of 38 undifferentiated specimens (50%) displayed positivity for C-kit (p>0.5). Conclusions: More than half of Retinoblastomas in this study expressed C-kit. The expression of Ckit in these retinoblastomas strongly correlated with histopathological features of worse prognosis including optic nerve and choroidal invasion.
TEDE
BV UNIFESP: Teses e dissertações
Khan, Tanweera S. "New Diagnostic and Therapeutic Approaches in Adrenocortical Cancer." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4243.
Повний текст джерелаThompson, Jennifer Jane. "Canine Mast Cell Tumours: Characterization of Subcutaneous Tumours and Receptor Tyrosine Kinase Profiling." Thesis, 2012. http://hdl.handle.net/10214/3652.
Повний текст джерелаPet Trust Foundation, Ontario Veterinary College
Young, Sonia Marie. "The receptor tyrosine kinase, c-KIT: its involvement in signal transduction and biological response / Sonia Marie Young." 2003. http://hdl.handle.net/2440/21963.
Повний текст джерелаAmmendments to chapter 9 and a journal article co-authored by the author in back pocket.
Includes bibliographical references (leaves 162-205)
xviii, 211 leaves : ill. (some col.), plates (some col.) ; 30 cm.
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.
Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2003
Young, Sonia Marie. "The receptor tyrosine kinase, c-KIT: its involvement in signal transduction and biological response / Sonia Marie Young." Thesis, 2003. http://hdl.handle.net/2440/21963.
Повний текст джерелаAmmendments to chapter 9 and a journal article co-authored by the author in back pocket.
Includes bibliographical references (leaves 162-205)
xviii, 211 leaves : ill. (some col.), plates (some col.) ; 30 cm.
Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2003
Tamlin, Vanessa Sarah. "KIT Mutations in Australian Canine Mast Cell Tumours and Correlations with Patient Prognostic Factors." Thesis, 2019. http://hdl.handle.net/2440/123488.
Повний текст джерелаThesis (Ph.D.) -- University of Adelaide, School of Animal and Veterinary Sciences, 2019
Smith, Amanda Melanie. "Targeting PP2A activation as a novel therapeutic strategy for receptor tyrosine kinase driven leukaemia." Thesis, 2014. http://hdl.handle.net/1959.13/1043096.
Повний текст джерелаThe receptor tyrosine kinases (RTK) c-KIT and FLT3 are overexpressed or mutated in acute myeloid leukaemia (AML) and numerous other cancers. Constitutive activation of these RTKs stimulates downstream kinase signalling cascades including PI3K/Akt, Ras/MAPK, and JAK/STAT, which lead to increased proliferation and leukaemogenesis. Although inhibition of c-KIT with imatinib mesylate (IM) has been successful in treating gastrointestinal stromal tumour (GIST) patients, responses in AML patients have been less favourable, largely due to intrinsically resistant kinase domain mutations. There are currently no clinically available, therapeutic compounds targeting c-KIT or FLT3 in AML. Considering around half of core-binding factor AML express c-KIT mutations and one third of all AML patients express FLT3 mutations, a greater understanding of the signalling pathways regulated by these RTKs is necessary to identify novel targets for improved therapy of these leukaemias. Protein phosphatase 2A (PP2A) is a fundamental cellular signalling molecule that regulates many of the signalling pathways deregulated in leukaemia. PP2A is a heterotrimeric enzyme composed of a catalytic (PP2A-C), scaffolding (PP2A-A) and one of a number of regulatory (PP2A-B) subunits. PP2A is a proposed tumour suppressor, regulated by interaction with regulatory B subunits, or one of a number of endogenous PP2A interacting proteins. The role of functional PP2A inactivation has recently been recognised as a mediator of oncogenic tyrosine kinase driven leukaemia. This thesis is the first to examine the role of PP2A inhibition in c-KIT and FLT3 driven leukaemogenesis. Utilising the FDCP.1 mouse myeloid cell line expressing imatinib-sensitive (V560G) or –resistant (D816V) mutant c-KIT, and the BaF3 murine lymphoblastic cell line expressing constitutively active FLT3-ITD (FLT3 with internal tandem duplication), I show for the first time that constitutive activation of c-KIT or FLT3 induces functional inactivation of PP2A tumour suppressive activity. Importantly, pharmacological reactivation of PP2A by FTY720 or AAL(S) was found to inhibit the growth and survival of cells expressing these mutant RTKs. Furthermore, I have shown that FTY720 mediated activation of PP2A induces apoptosis of AML patient blasts expressing FLT3 mutations, compared to patient cells expressing the WT FLT3 receptor. PP2A inhibition was found to be associated with reduced protein, but not mRNA, expression of PP2A structural and regulatory subunits, and this is functionally important as over-expression of exogenous PP2A-A induced apoptosis in these cells. PP2A inhibition was further associated with the expression of novel variants of the endogenous PP2A inhibitory protein, SET. These novel variants were also identified in AML patient blasts. Further investigations showed that these novel variants alter the subcellular localisation of SET, and its co-localisation with PP2A. Investigations into the mechanism of action of the PP2A activating compound, FTY720, found that FTY720 alters the expression and sub-cellular location of these novel SET proteins, suggesting that they are functionally important in the cellular response to FTY720. Finally, I showed that PP2A activators synergise with clinically relevant tyrosine kinase inhibitors to inhibit colony formation and proliferation. Therefore, the work in this thesis significantly contributes to our understanding of the role of PP2A as a tumour suppressor in AML, and suggests thatPP2A activators present a novel therapeutic strategy for RTK driven leukaemias used as a monotherapy or in conjunction with targeted tyrosine kinase inhibitors.
Subramanian, Aparna. "The BMP4 stress erythroid pathway and the Kit receptor tyrosine kinase in Friend virus induced erythroleukemia." 2005. http://etda.libraries.psu.edu/theses/approved/WorldWideIndex/ETD-963/index.html.
Повний текст джерелаCaruana, Georgina. "The transforming potential and functional analysis of the c-Kit receptor tyrosine kinase and its natural occurring isoforms / by Georgina Caruana." Thesis, 1996. http://hdl.handle.net/2440/18708.
Повний текст джерелаBibliography: leaves 157-214.
iv, 214, [131] leaves, [19] leaves of plates : ill. (some col.) ; 30 cm.
The function of receptor tyrosine kinase, c-Kit is examined in relation to the role of receptor levels in factor dependence and cell transformation and the function of several naturally occurring isoforms of the human c-Kit receptor were analyzed by expressing cDNA encoding these isoforms in murine cells.
Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1996
Ming-JungLin and 林明蓉. "Explore the Growth Inhibitory Effect and Mechanisms of Novel Tyrosine kinase Inhibitors on Mutant KIT-expressing Gastrointestinal Stromal Tumor." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/08821740439736135940.
Повний текст джерела國立成功大學
分子醫學研究所
102
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumors of the gastrointestinal tract. GISTs frequently exhibit gain-of-function KIT mutations (70-80% of GISTs), which leads to constitutive activation of the KIT tyrosine kinase receptor in the absence of its binding ligand, stem cell factor (SCF). The most common KIT mutations are located at exon 11 (≈80%) followed by exon 9 (≈10-15%) and exons 13, 14 or 17 (≈5%). Clinically, imatinib mesylate (IM), sunitinib malate (SU), regorafenib, a sorafenib-derived compound, are multi-tyrosine kinase inhibitors (TKIs), are the current standard treatments for patients with unresectable and/or metastatic GIST. However, those drugs have limitations: experience disease progression, associated with the acquisition of secondary mutations, and unsatisfactory median progression-free survival. Therefore, it is important to explore much suitable compound for advanced gastrointestinal stromal tumor. In this study, we aim to evaluate the growth inhibitory effects and molecular mechanisms of a novel TKI from the Institute of Biotechnology and Pharmacology, National Health Research Institutes, the 1J373S1 that was initially designed as a FLT-3 inhibitor, on IM and/or SU resistance GIST cells. The 1J373S1 shows activity on inhibiting the KIT phosphorylation and proliferation of KIT mutated GIST cells, including IM-sensitive exon13 mutated GIST882, IM-resistant/sunitinib-sensitive exon 11/13 doubly mutated GIST430, IM/SU-resistant/nilotinib-sensitive exon 11/17 doubly mutated GIST48. The superiority of 1J373S1 on inhibiting the activation of KIT mutant proteins was confirmed in an in vitro cell-based platform consisting of a series of COS-1 cells expressing various KIT cDNA constructs encoding common primary ± secondary mutations observed in clinical GISTs. Interestingly, TKI treatment usually resulted in G0 arrest in sensitive cell lines (SU for GIST 430 and nilotinib for GIST48), however, 1J373S1 treatment resulted in G2/M-arrest in both GIST48 and GIST430 cells and also induces GIST cell lines apoptosis. In addition, we have explored that 1J373S1 treatment can induce senescent signals: p53, p21, p16, E2F, β-galactosidase signal up-regulation of exon 11/17 doubly mutated GIST48. In future work, we shall explore the molecular mechanisms of growth inhibition GIST cells further more.
Muirhead, Karla Jaimee. "The role of KL and C-Kit in primordial follicle activation in the juvenile rabbit ovary." Phd thesis, 2005. http://hdl.handle.net/1885/150654.
Повний текст джерелаYuan-ShuoHsueh and 薛元碩. "Establishment of a Drug Screening Platform to Study the Effects and Mechanisms of Tyrosine kinase Inhibitors and a Novel HSPAA1 Inhibitor (NVP-AUY922) on Mutant KIT-expression GIST." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/39080318730110331378.
Повний текст джерела國立成功大學
臨床藥學與藥物科技研究所
101
Background Advanced gastrointestinal stromal tumors (GIST), a KIT oncogene-driven tumor, on imatinib mesylate (IM) treatment may develop secondary KIT mutations to confer IM-resistant phenotype. Second-line sunitinib malate (SU) therapy is largely ineffective for IM-resistant GISTs with secondary exon 17 (activation-loop domain) mutations. Nowadays, several KIT tyrosine kinase inhibitors (TKIs) and heat shock protein 90 (HSP90AA1) inhibitors are under investigation for IM and/or SU-resistant GIST patients. However, there is no notable improvement. In this study, we used commercial available TKIs and a new class of HSP90AA1 inhibitor, NVP-AUY922 (AUY922), to evaluate their potencies for treatment on IM and/or SU-resistant GISTs and to clarify the detailed mechanisms. Methods and Results First, we established an in vitro cell-based platform consisting of a series of COS-1 cells expressing KIT cDNA constructs encoding common primary±secondary mutations observed in GISTs, to compare the activity of several commercially available TKIs on inhibiting the phosphorylation of mutant KIT proteins at their clinically achievable plasma steady-state concentration (Css). The inhibitory efficacies on KIT exon 11/17 mutants were further validated by growth inhibition assay on GIST48 cells, and underlying molecular-structure mechanisms were investigated by molecular modeling. Our results showed that SU more effectively inhibited mutant KIT with secondary exon 13 or 14 mutations than those with secondary exon 17 mutations, as clinically indicated. On contrary, at individual Css, nilotinib and sorafenib more profoundly inhibited the phosphorylation of KIT with secondary exon 17 mutations and the growth of GIST48 cells than IM, SU, and dasatinib. Molecular modeling analysis showed fragment deletion of exon 11 and point mutation on exon 17 would lead to a shift of KIT conformational equilibrium toward active form, for which nilotinib and sorafenib bound more stably than IM and SU. In the other hand, we demonstrated that AUY922 is effective in inhibiting the growth of GIST cells expressing mutant KIT protein, the IM-sensitive GIST882 and IM-resistant GIST48 cells. The growth inhibition was accompanied with a sustained reduction of both total and phospho-KIT proteins and the induction of apoptosis in both cell lines. Surprisingly, AUY922-induced KIT reduction could be partially reversed by pharmacological inhibition of either autophagy or proteasome degradation pathway. The blockade of autophagy alone led to the accumulation of the KIT protein, highlighting the role of autophagy in endogenous KIT turnover. The involvement of autophagy in endogenous and AUY922-induced KIT protein turnover was further confirmed by the colocalization of KIT with MAP1LC3B-, acridine orange-, or SQSTM1-labeled autophagosome, and by the accumulation of KIT in GIST cells by silencing either BECN1 or ATG5 to disrupt autophagosome activity. In addition, AUY922 could reduce KIT mRNA at transcription level without affecting its mRNA stability. Further studies showed that AUY922 treatment would reduce the nuclear activities and protein levels of several transcription factors, such as CEBP, TP53, RELA, and HIF1A in GIST cells. Experiments using DNA affinity precipitation and chromatin immune-precipitation assays showed that TP53 could bind on KIT promoter region (from -365 to -30 nucleotides upstream of the transcriptional start site), and its binding activity was significantly reduced after AUY922 treatment. Conclusions Taken together, we show that nilotinib and sorafenib are more active in IM-resistant GISTs with secondary exon 17 mutation than SU that deserve further clinical investigation. Moreover, the results of AUY922 not only highlight its potential application for the treatment of KIT-expressing GISTs, but also provide the first evidence for the involvement of autophagy in endogenous and HSP90AA1 inhibitor-induced KIT degradation in GIST882 and GIST48 cells.